基于合成致死策略寻找ARID1A突变肝细胞癌的治疗靶点

ARID1A编码的BAF250a蛋白是SWI/SNF(SWItch/Sucrose Non-Fermentable)染色质重组复合物BAF(BRG1-associated factors)的亚基之一,参与改变染色体的结构和可接近性。ARID1A在肝细胞癌(hepatocellular carcinoma,HCC)中的突变率高达13%,但目前尚无有效的治疗药物。本研究旨在利用合成致死策略寻找携带ARID1A突变HCC的治疗新靶标。首先,本研究通过分析ARID1A突变与肿瘤恶性程度的相关性发现ARID1A突变的肿瘤恶性度增加;进而分析Achilles和NCI-60癌症细胞系中ARID1A突变和野生型细胞系的基因表型值(gene phenotype value,GPV)和高表达基因,获得ARID1A突变细胞低GPV和高表达的重叠基因,再扩大样本使用CCLE(Cancer Cell Line Encyclopedia)细胞系的高表达基因进行重叠基因分析;最后并在TCGA(the Cancer Genome Atlas)肝癌数据库中进行筛选,获得116个潜在的ARID1A合成致死基因。本研究运用生物信息学方法计算获得多个ARID1A的潜在合成性致死基因,为ARID1A突变HCC患者提供新的治疗靶点,也为靶向药物研发提供了新靶标和新策略。

Identification of Synthetic Lethal Targets in ARID1A-mutant Liver Cancer

ARID1A,encoding BAF250 a protein,is a subunit of the SWI/SNF chromosome remodeling complex,which modulates DNA accessibility and chromatin conformation.ARID1A has been identified as one of the most frequently mutated genes in human cancers,especially in HCC(13%).The new druggable targets and therapeutic agents are thus urgently demanded for ARID1A mutant HCC patients.The aim of this study is to identify the druggable targets for ARID1A mutant HCC patients with synthetic lethal strategy.We first analyzed the correlation between ARID1A mutation and tumor malignancy and found that the ARID1A mutation is highly associated with the malignancy of the tumor.We then identified 116 potential synthetic lethal genes of ARID1A by comparing the gene phenotype value of Achilles cancer cells and high expression genes of NCI-60 and CCLE between ARID1A mutation and wild type cell lines,which were further validated in TCGA database.This study identified the synthetic lethal genes of ARID1A,which provides potential druggable targets to further develop the therapeutic agents for ARID1A mutant HCC patients.